Solid State Kinetics of Nitrosation Using Native Sources of Nitrite -Pub

Publication " Solid State Kinetics of Nitrosation Using Native Sources of Nitrite" by Carloni et al.

While many reactive species are known to cause N -nitrosation, trace nitrite (NO2−), which may be present in several excipients, is a source of nitrosating agents in pharmaceutical formulations. In this study we have found that the salt form of NO2− can influence the kinetics and final amount of nitrosamine being formed. Using native levels of NO2-, which is most likely present as ammonium nitrite (NH4NO2), in microcrystalline cellulose (MCC), we have determined the kinetics of nitrosamine formation in solid state with dimethylamine (DMA) substrate present in metformin, used as model compound. It was found that the competing degradation of NH4NO2 into N2 and H2O limited the amount of nitrosamine formation to a great extent. Modelling the kinetic data predicted reaching at maximum ∼1.6% conversion over a hypothetical 3-year shelf-life. These results also showed that using other sources of NO2−, such as NaNO2, as a spiking reagent may lead to unrealistic worst-case situations when the main form of NO2- in the DP under evaluation may be NH4NO2. As well, measuring NO2− in freshly manufactured excipients containing NO2− potentially as NH4NO2 may lead to biased high NO2− content, which is not representative of the actual amounts present at the time of DP manufacture.

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Modified NAP Test: A Simple and Responsive Nitrosating Methodology for Risk Evaluation of NDSRIs



Nitrosamines have been recognized as one of the cohorts of concern as per ICH M7. In recent years, the regulatory focus has shifted from common nitrosamines to nitroso-impurities of drug products. Thus, the detection and quantification of unacceptable levels of nitrosamine drug substance-related impurities are of great concern for analytical scientists during drug development. Moreover, risk assessment of nitrosamines is also an essential part of the regulatory filling. For risk assessment, the Nitrosation Assay Procedure suggested by WHO expert group in 1978 is being followed. However, it could not be adopted by the pharmaceutical industries due to the limitation of drug solubility and artefact formation in the test conditions. In this work, we have optimized an alternative nitrosation test to investigate the likelihood of direct nitrosation. The technique is simple, where the drug solubilized in an organic solvent is incubated at 37°C with a nitrosating agent named tertiary butyl nitrite in a 1:10 molar ratio. LC-UV/MS-based chromatographic method was developed to separate drug substances and respective nitrosamine impurities using the C18 analytical column. The methodology was successfully tested on five drugs with varying structural chemistry. The procedure is straightforward, effective, and quick for the nitrosation of secondary amines. This modified nitrosation test and WHO prescribed nitrosation test have been compared and found that the modified methodology is more effective and time-saving.